Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration

PLoS One. 2014 Nov 13;9(11):e112142. doi: 10.1371/journal.pone.0112142. eCollection 2014.


Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Calpain / physiology
  • Cell Death / genetics
  • Cell Death / physiology*
  • Cyclic GMP / physiology
  • Disease Models, Animal
  • Histone Deacetylases / physiology
  • Light Signal Transduction / genetics
  • Mice
  • Mutation
  • Poly Adenosine Diphosphate Ribose / physiology
  • Poly(ADP-ribose) Polymerases / physiology
  • Rats
  • Retinal Degeneration / genetics
  • Retinal Degeneration / physiopathology*


  • Poly Adenosine Diphosphate Ribose
  • Poly(ADP-ribose) Polymerases
  • Calpain
  • Histone Deacetylases
  • Cyclic GMP

Grant support

This work was supported by the Kerstan Foundation, Deutsche Forschungsgemeinschaft [DFG PA1751/1-1, 4-1], Alcon Research Institute, European Commission [DRUGSFORD: HEALTH-F2-2012-304963; PANOPTES: NMP4-SL-2010-246180], German Ministry of Education and Research [BMBF HOPE2 - FKZ 01GM1108A], Centre for Integrative Neuroscience [CIN pool project 2009-20], Kronprinsessan Margaretas Arbetsnämnd (KMA), Stiftelsen Olle Engkvist Byggmästare, The Swedish Research Council 2009-3855, and Stiftelsen för Synskadade i f.d. Malmöhus län. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.